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Synthesis of 2-Thiocarbohydrates and Their Binding to Concanavalin A Prashant Pavashe, Elangovan Elamparuthi, Cornelia Hettrich, Heiko M. Möller, and Torsten Linker J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00987 • Publication Date (Web): 12 Aug 2016 Downloaded from http://pubs.acs.org on August 23, 2016
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The Journal of Organic Chemistry
Synthesis of 2-Thiocarbohydrates and Their Binding to Concanavalin A Prashant Pavashe, Elangovan Elamparuthi, Cornelia Hettrich, Heiko M. Möller, and Torsten Linker* Department of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany
O BnO
O
NH 4SCN CAN, MeOH 62-93%
BnO
hexoses, pentoses, disaccharides
OMe SCN
O
Na NH 3 67-78%
HO
OMe SH
manno: strong binding to Con A
ABSTRACT: A convenient and general synthesis of 2-thiocarbohydrates via cerium ammonium nitrate oxidation of the thiocyanate ion is described. Radical addition to glycals proceeds with excellent regio- and good stereoselectivities in only one step, deprotection affords water-soluble 2-thio saccharides. Binding studies to Con A have been performed by isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR spectroscopy. The 2thiomannose derivative binds even stronger to Con A than the natural substrate, offering opportunities for new lectin or enzyme inhibitors.
ACS Paragon Plus Environment
The Journal of Organic Chemistry
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Analogs of naturally occurring carbohydrates are of current interest as enzyme inhibitors and have
found
various
applications
in
chemistry,
biology,
and
medicine.1
Especially
thiooligosaccharides2 have been intensively studied, due to their stability against acidic or enzymatic hydrolysis. For instance, thio analogs of kojibioside were obtained already 20 years ago,3 but new approaches have been published very recently.4 Furthermore, thiosugars exhibit antiviral activities5 and even simple 5-thio-D-glucose potentiates the hyperthermic killing of cancer cells.6 Although thiosugars are produced in biosynthetic pathways,7 their chemical synthesis requires many steps. The main strategies for the introduction of sulfur into monosaccharides are opening of epoxides (anhydro sugars)8 and SN2 reactions9 of good leaving groups with thio nucleophiles. Thus, all positions of hexoses have been substituted by these methods.10 Additionally, 2thiosugars are available by Michael additions11 and 1-2 sulfur rearrangements12 as well. However, the synthesis of the precursors is tedious, requires many steps or expensive starting materials, and overall yields are often moderate. Herein we describe a general and convenient new entry to 2thiosugars by radical additions to glycals in only few steps and present binding studies to concanavalin A (Con A) as a model system for the first time. Glycals 1 are suitable precursors for many transformations in carbohydrate chemistry and can be synthesized on a multigram scale with acetyl (Ac) or benzyl (Bn) protecting groups.13 We have been interested in additions of CH-acidic compounds (e.g. malonates or nitromethane) to their 2position in the presence of cerium ammonium nitrate (CAN) for many years.14 More recently, we described the formation of C–P bonds by this oxidant.15 Thus, based on the pioneering azidonitration of sugars by Lemieux,16 we became interested in other heteroatom oxidations for applications in carbohydrate chemistry. Thiols cannot be oxidized directly by CAN, due to disulfide formation, however thiocyanates react conveniently with CAN to generate the ACS Paragon Plus Environment
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The Journal of Organic Chemistry
corresponding radicals, suitable for additions to simple alkenes and arenes.17 In carbohydrate chemistry thiocyanates have only been used for nucleophilic substitutions.8a,18 We therefore investigated the reaction of various glycals 1 with ammonium thiocyanate (2), which is a cheap commercially available reagent, in the presence of CAN (Table 1). No conversion could be achieved with acetyl-protected glucal 1a (entry 1), presumably due to the higher electrophilicity of thiyl radicals19 and the low electron density of double bonds of acetylprotected glycals, which we determined by cyclic voltammetry.20
Table 1. Addition of Ammonium Thiocyanate (2) to Glycals 1a O RO OR
CAN MeOH, 0 °C
glycal
1
RO
O
O +
RO
1 entry
OMe
O
NH 4SCN (2)
SCN
OMe
RO
SCN
OR
OR
anti-3b
syn-3b
R
β-anti-3 (%)c
α-anti-3 (%)c
syn-3 (%)c
Ac
β-gluco-3a (
